Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Hah N, Danko CG, Core L, Waterfall JJ, Siepel A, Lis JT, et al. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 2011;134:1–13.Blockade of hormone receptors in estrogen receptor–positive breast cancers is one of the first and most durable of targeted therapies for cancer. Ligand binding induces dimerization and nuclear translocation of the estrogen receptor, subsequently engaging all 3 RNA polymerases and initiating a complex transcriptional program of primary and secondary transcripts. To clarify the immediate effects of estrogen signaling, and to generate a comprehensive map of estrogen signaling in breast cancer, Hah and colleagues used a combination of global nuclear run-on and sequencing of both the position and the orientation of all engaged RNA polymerases in MCF7 breast cancer cells. Over one quarter of all cellular transcripts were altered in response to estrogen treatment, including striking coordination of both sense and antisense transcripts for ∼600 genes (consistent with antisense attenuation of the corresponding sense transcripts) and ∼3,000 intergenic transcripts. A total of 3,100 transcripts corresponded to proteins, with half of these showing regulation within 10 minutes of estrogen treatment. Nearly 40% of all microRNAs in the genome were regulated in response to estrogen.Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 2011;473:230–3.Notch signaling represents a fundamental developmental pathway that is critical to hematopoiesis. Whereas decreased Notch signaling has been reported to drive solid tumors in mouse models, only mutational activation of this pathway has been found in human malignancies (acute T-cell leukemias). Klinakis and colleagues now demonstrate that mutational inactivation in various Notch signaling components drives mouse models of chronic myelomonocytic leukemia (CMML). Is this result relevant to human CMML? Analyses of 42 patient samples identified heterozygous somatic mutations in Notch pathway members in 5 cases. These mutations were observed in patients whose tumors also showed mutation in RAS, ASXL1, TET2, and JAK2, suggesting cooperation in transformation. Thus, whereas Notch pathway inhibition may have a role in the treatment of acute T-cell leukemia, targeted activation (rather than inactivation) of this pathway may be important for malignancies of granulocytes and monocytes.Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011;71:3196–201.Recognized limitations of conventional chemotherapy include toxicity and the inevitable development of therapy-resistant tumors. One explanation for the resistance phenotype is the cancer stem cell (CSC) hypothesis, which suggests that heterogeneous tumors comprise a small fraction of tumor-forming, self-renewing CSCs intermingled with the majority of the tumor population consisting of non–tumor-forming cancer cells. When exposed to repeated administration of chemotherapeutic drugs, the non–tumor-forming cancer cell population is reduced (which is associated with a reduction in tumor size), whereas the CSCs survive and can then repopulate the tumor resulting in further resistance to therapy. In these contexts, an ability to target CSCs for death represents a potentially powerful way to both prevent tumor repopulation (reflected by an extended delay in relapse time) and enhancing sensitivity to chemotherapy. Iliopoulos and colleagues present evidence showing that combining chemotherapy with metformin, a first-line drug for treating diabetes, promotes selective killing of CSCs in multiple genetically distinct breast cancer cell lines. Oral administration of metformin with a variety of standard chemotherapeutic agents (paclitaxel, carboplatin, or doxorubicin) suppresses tumor growth. The use of metformin also permitted a lower dose of chemotherapy, resulting in tumor regression and delayed relapse. Moreover, the combination of metformin and doxorubicin prevented relapse in xenografts that were induced by diverse cancer cell types, including prostate and lung cancer cell lines. Further studies are required, but these provocative findings suggest that metformin might have broad applications in multiple clinical settings when combined with standard chemotherapy, improving therapeutic response by reducing the dose of chemotherapy required to elicit a response. (Image from cited article courtesy of publisher.)De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 2011;208:469–78.Many studies of the cancer microenvironment focus on the tumor-promoting or tumor-inhibiting roles of a particular immune, fibroblast, or endothelial cell, but few studies tackle the reality of complex and dynamic interactions between the many different cells that comprise a malignant tumor. Type 2 helper (Th2) lymphocytes are abundant in the fibrotic stroma that is characteristic of human pancreatic cancer. De Monte and colleagues hypothesized that tumor-resident dendritic cells, conditioned by local factors, may be able to favor differentiation of tumor-specific Th2 cells in the draining lymph nodes. They also had an idea that an interleukin (IL)-17-like cytokine, thymic stromal lymphopoietin (TSLP), might be involved. In an experiment conducted entirely with human cells and tissues, the authors found a significant association between tumor Th2 cell infiltrates and poor prognosis, with the ratio between Th2/Th1 cells in tumor biopsies being independently predictive of patient survival. Then, using biopsies, isolated cells, and short-term primary cultures, the authors looked at such cytokines as TNFα (mainly made by the tumor cells), IL-1β (made by tumor and stromal cells), and TSLP (made by cancer-associated fibroblasts) forming a picture in which tumor cell-produced cytokines stimulated TSLP production by the fibroblasts. TSLP was already known to induce Th2 responses through dendritic cell activation. This observation was confirmed both in vitro and by analysis of draining and non-draining lymph nodes. But how would the resulting Th2 cells be attracted to the tumor microenvironment? The obvious candidates were the Th2 attracting chemokines CCL17 (made by infiltrating immune cells) and CCL22 (made by the malignant epithelial cells). The final model emerging from these experiments is therefore that inflammatory cytokines produced by the malignant cells (probably downstream of oncogenic mutations) stimulate fibroblasts to make TSLP. TSLP activates/matures resident tumor dendritic cells that migrate to draining lymph nodes, where they, in turn, activate CD4+ T cells toward a Th2 phenotype. Th2-attracting chemokines bring those cells back to the tumor, where they have a major tumor-promoting influence. This model of the cytokine/chemokine network implicated in tumor-promoting Th2 responses provides further support for targeting some of these mediators as part of a multimodal approach for treatment of this challenging disease.Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 2011 May 8. [Epub ahead of print].Mutations in c-abl or c-kit can be used to predict outcomes for patients with chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST), respectively, but unfortunately can also result in therapeutic resistance to imatinib mesylate, a kinase inhibitor that blocks ABL and KIT kinase activity. Some patients with GIST whose tumors harbor c-kit mutations exhibit unexpected long-term responses to imatinib indicating involvement of alternative mechanisms in response to therapy. The therapeutic response to imatinib is in part mediated by natural killer (NK) and dendritic cells (DC). Delahaye and colleagues sought to understand the role of NK cells in regulating responses to imatinib in KIT-mutant GIST tumors. The authors conducted a retrospective analysis of 80 patients with GIST and evaluated expression of alternatively spliced isoforms of a major NK receptor, NKp30, involved in recognition of tumor cells and DCs. Significantly, both patients with GIST and healthy individuals can express distinct NKp30 isoforms; an immunosuppressive variant, NKp30c; or 2 immunostimulatory isoforms, NKp30a or NKp30b. They found that expression of NKp30c was highly prognostic in patients with GIST and associated with reduced survival. They also found that tumors from these individuals exhibited decreased NKp30-dependent CD107a and TNFα release as well as defective IFN-γ and interleukin (IL)-12 secretion, all of which are important aspects of NK-DC cross-talk that were restored by blockade of IL-10. These results provide provocative and compelling evidence that the efficacy of imatinib, and possibly other targeted therapies, involves immune-regulated pathways, and specifically NK cells. More generally, these findings imply that therapies that enhance NK cell activity may be beneficial to the clinical efficacy of targeted therapies, whereas those that suppress NK cell activity may be detrimental to therapeutic efficacy. Future experiments are required to determine whether these results can be generalized to different types of tumors and other forms of targeted therapy.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.